STAS was identified, by the 2015 WHO classification, as a new method of invasion in lung adenocarcinoma, with poor prognosis. Blood vessel co-option is a mechanism by which spreading intraalveolar tumor cells connect to the surrounding vasculature to survive. The aim of this study was to visualize the dynamic mechanism of blood vessel co-option using a high resolution and high-quality 3D reconstruction, and multiplex immunofluorescence (IF).

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Method

A 3D reconstruction image of a case of invasive lung adenocarcinoma with extensive STAS was performed on the formalin fixed paraffin-embedded (FFPE) block. 150 serial sections were obtained by the automated sectioning system AS410 (DNS. Ltd, Japan), and stained with H&E (100 slides), and multiplex IF (30 slides) for CD31, type IV collagen, TTF-1 and E-Cadherin to assess the relation between STAS and the surrounding lung parenchyma and vasculature. The IF stained sections were scanned with 0.33um/pixel by Panoramic P250 Flash (3D Histech Ltd, Hungary) Whole Slide Imaging Scanner (WSI). The WSIs were reconstructed into 3D exported to Imaris 8.0 (Bitplane, MA, US) for signal assessment.

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Result

Serial 3D image analysis identifies the presence of STAS mainly in the form of micropapillary clusters. The multiplex IF staining highlighted the co-option which was determined by the spread and then attachment of STAS (TTF-1 and E-Cadherin positive) to distant alveolar wall capillaries (CD31 positive) with preservation of the alveolar wall (figure). This relation between STAS and the surrounding lung parenchyma was visualized in all serial sections of the whole FFPE block thickness.

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Conclusion

The survival of STAS, beyond the tumor edge, in lung adenocarcinoma is a viable mechanism for tumor recurrence. The combination of the high resolution and high-quality 3D reconstruction and multiplex immunofluorescence in our study, supports the concept that dynamic blood vessel co-option is a mechanism for STAS survival.

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